Differential regulation of JNK activation and MKP-1 expression by peroxovanadium complexes

Abstract

Bisperoxovanadium complexes have been identified as insulinomimetic agents and protein tyrosine phosphatase inhibitors. The aim of the present study was to examine the effects of the most potent bisperoxovanadium complex, potassium bisperoxo (1,10-phenanthroline) oxovanadate (V) [bpV(phen)], on expression and activation of c-jun N-terminal protein kinases (JNK) and on expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) in different cell lines. We compared the effects of bpV(phen) with the effects of tumor necrosis factor-α (TNF-α), a known regulator of JNK phosphorylation and inducer of MKP-1. Treatment with bpV(phen) causes significant and sustained down-regulation of MKP-1 expression both in PC12 and HeLa cells. In contrast, TNF-α induces MKP-1 expression in PC12 cells and does not alter MKP-1 expression in HeLa cells. Both bpV(phen) and TNF-α induce MKP-1 expression in OVCAR-3 cell line but with different dynamics: TNF-α causes transient and bpV(phen) sustained induction of MKP-1 expression. Temporal pattern of level of MKP-1 expression correlates with the regulation of JNK phosphorylation by bpV(phen) and TNF-α in PC12 cells. However, no detectable phospho-JNK signal is observed in either OVCAR-3 or HeLa cells treated with bpV(phen). In contrast, TNF-α causes strong and sustained JNK phosphorylation in OVCAR-3 cell line, and strong but transient JNK activation in HeLa cells. BpV(phen) and TNF-α does not alter JNK expression in any of the cell lines studied. We demonstrate that the effect of two stressors, bpV(phen) and TNF-α, on MKP-1 expression and JNK phosphorylation are strikingly different, depending on the cell type. These results suggest the possible role of MKP-1 in regulation of JNK phosphorylation in both PC12 and OVCAR-3 cell lines treated with bpV(phen).